Puberty and Reproductive Senescence

Developmental Timing of Reproductive Organs in Humans and Livestock

• humans: should occur late in 3rd trimester before birth

  • testes should descend into the scrotum, doesn’t always happen

Target Tissues of Testosterone and Metabolites: Importance on male Sexual Differentiation

Proper testicular descent is critical for full fertility

Testes need to be cooler than normal body temperature for proper spermatogenesis to occur (testicular descent is important…)

• Testosterone, DHT, & INSL3 (Insulin-like peptide-3) induce testicular descent in the fetus, involving passage through the inguinal canal into the scrotal sac

  • descent from inside the abdomen (where they developed), all the way down into the inguinal canal & into the scrotum

• Guided by a band of tissue called the gubernaculum

  • sits at the base of scrotum

  • as it shrinks & contracts, it pulls the spermatogenic cord & pulls the testicle into the scrotum

  • if that fails to happen, have a condition called cryptorchidism

• Cryptorchidism

  • bilateral or unilateral

  • if this happens in a human, doctors will just wait a few weeks to see if it occurs on its own, if not, it needs to be a surgical procedire bc in humans, if you leave the testes inside the body, it increases the risk of testicular cancers

  • get it out

  • if it’s still inside your body, it’s too hot & it won’t properly make sperm cells (subfertile)

• Inguinal Hernia:

  • part of testis can get pushed out through inguinal canal in an inguinal hernia

  • some of testis in scrotum

Male and female brains are different: Role of Alpha-fetoprotein

• starts in fetal development

• reproductive center of the brain in the hypothalamus

• alpha-fetoprotein, female

  • protein produced in the fetus

  • can bind steroid with very high affinity

    • specifically estradiols

  • when estrogens from both the fetal ovary & the maternal system are bound by alpha-fetoprotein, they can’t cross the BBB

Male and female brains are different: Role of Alpha-fetoprotein 2

• Male

  • testosterone is produced at very high levels

    • when it’s being produced, alpha-fetoprotein doesn’t bind testosterone like it does estradiol

    • a large amount of this lipophilic hormone testosterone can cross through the BBB where it is aromatized into estradiol

      • as it does so, it prevents the development of the surge center of the hypothalamus

  • fundamentally, the structure & function of the hypothalamus is different in males & females even during fetal development

  • testosterone being produced in fetal testis is what drives this change in our brains

• reason it does this is becausse it can bind estrogen but it cannot bind with high affinity to testosterone

• makes hypothalamus develop differently between males & females

Gonadal hormone levels change across lifespan (estrogen, progesterone, testosterone)

• Postnatal testosterone secretion surges briefly (1-3 months), then decreases to baseline until puberty

• hormone levels across males & females will change dramatically over the time period b/w conception & puberty

Timing of Puberty is Complex

• 50-80% of influence on age of puberty is genetic

  • vast majority of the influence on age of puberty

  • lots of different inputs from environment that can push that genetic control of when puberty occurs

    • lower (precocious puberty) or higher (delayed)

  • a lot of how soon/late a person enters puberty determined by this

  • most of impact, what happened to your ancestors you’’ll ve very close to that same age

• Nutrition can play a significant role

  • Obesity can accelerate the onset of puberty

  • can move start age of puberty

• certain signals from environment/body that can begin to push puberty faster/make it earlier onset

• there’s also low energy availability signals from either intense exercise or malnutrition that can delay the onset of puberty in males & females

• components of the hypothalamus begin to become activated, were quiescent prior to puberty

• ultimately, it’s this stimulation of these GnRH-releasing neurons in the hypothalamus from these kisspeptin secreting neurons in the arcuate nucleus of the hypothalamus that will ultimately lead to the start of the hypothalamic-pituitary axis that will start to stimulate the gonads to become functional

  • functional meaning start producing gametes & hormones that go along with that

• many things can impact onset of puberty

  • leptin: amount of adiposity, tells a person that they’re big enough to start reproducing/have enough energy sources to start reproducing

• don’t want to produce children until you’re physically ready to have them

Model for the metabolic control of GnRH secretion by peripheral metabolic hormones

Pubertal changes in girls and boys

variable

Male Hypothalamus-Pituitary-Gonadal (HPG) Axis

Hypothalamus is the master reproductive control center (releases lots of different hormones that can control anterior pituitary)

• Controlled release of GnRH leads to control of FSH and LH from the anterior pituitary

  • GnRH acts on anterior pituitary to release these gonadotropins

• Gonadotrope release of gonadotropins (FSH and LH) control function of gonads

  • Hormone synthesis and secretion

  • Sperm production

  • FSH and LH will act on Sertoli cells & on Leydig cells to stimulate spermatogenesis

Hypothalamic activation of puberty

The anterior pituitary of pubertal males and females is more sensitive than prepubertal subjects to GnRH resulting in increased secretion of LH

• at puberty, that’s when your anterior pituitary starts to bevome responsive

• if you inject GnRH in pre-pubertal males, nothing happens (male or females)

• if you inject it as they begin to enter puberty, you get a response, but not nearly as much of a response as if you give it during the adult phase

  • all that tells us is cells of the anterior pituitary aren’t quite ready

    • they’ve been given the hormone, but those cells of the anterior pituitary still haven’t developed to a point where they can respond until after puberty

Puberty in Males

• Ages 9-14

• Adrenarche (DHEAS)

  • start to see development of pubic hair

• Increased GnRH → increased LH (LH stimulates Leydig cells in the testes to start producing more & more testosterone)

  • Increased LH → increased testosterone

  • First sign is testicular enlargement

    • Darkening of scrotum

    • Pendulous

  • Penile growth follows about a year later

    • May continue for several years

• Declining melatonin leads to increased GnRH

  • Up to 75% drop in melatonin before onset of puberty

  • before inc. of GnRH

    • don’t know why

    • marker, can see it happen in males

Testosterone effects are numerous

Androgenic (virilizing) → testosterone is a powerful hormone, has tremendous adrenergic effects

• Prenatal external genitalia and accessory glands development

• Prenatal testicular descent into scrotum

• Pubic, axillary and body hair development

• Growth of larynx

• Hair loss in temporal region of scalp

• Sperm production

• Libido and potency

• Beard growth

Testosterone Effects

Anabolic (cell growth)

• Pubertal growth spurt

• Bone lengthening and growth plate closure

  • growth plate will be fused due to the effects of androgens

• Increased muscle mass

• Positive nitrogen and electrolyte balance

• Increased red cell production

• Increased Basal Metabolic Rate

• Renal and salivary gland enlargement

• Decreased subcutaneous fat

Puberty in males occurs in specific stages

Specific age at each stage varies considerably

• as you move through puberty, get closer & closer to the adult form

HPG axis hormone fluctuations in males

• driven by endocrine system

• every time GnRH is released, FSH & LH are released from the anterior pituitary

  • happens every 3-6 hours from the time a male hits puberty until they die, never fully stops & we get a pulse of GnRH

Testosterone release in adult males is pulsatile

• that pulse of GnRH & the subsequent pulse of LH will immediately cause testosterone levels to rise as well because LH is going to bind to its receptor on the Leydig cells & that receptor is then going to trigger the production of more testosterone

Age-dependent Changes in Male Androgen Function

Complications from reduced androgen output throughout life:

• Reduced fetal androgen → intersex or sex reversed phenotype

• Reduced adolescent/pubertal androgen → decreased maturation of reproductive organs and secondary sex characteristics

• Reduced post-pubertal androgens → decreased spermatogenic output

• blue line: sperm production

  • sperm production coincides with increased amount of testosterone & falls as testosterone production decreases with old age

Endocrine Changes with Aging in Males

• SHBG continues to increase as males get older & older

  • causes our free testosterone levels to decline

  • free testosterone is the part that actually is functional

Loss of Androgens: Andropause

• males reach end of reproductive lifespan

• understand impact of losing testosterone as you get older

  • how it affects the different components of your physiological system

  • men don’t become infertile, become less fertile as they increase in age

How would you treat andropause?

• What are potential side effects of treatment?

Testosterone Therapy

• Testosterone replacement therapy is relatively common (Androgel, Testim)

  • andropause is basically failure to produce enough free testosterone

  • testosterone is a lipophilic hormone, it can be delivered through the skin

• Delivered in a gel, patch, or shot

• Oral delivery is not as effective

• Testosterone replacement is controversial due to potential side effects

  • Sleep apnea

  • Acne

  • Benign Prostatic Hyperplasia (BPH)

  • Breast enlargement

  • Polycythemia and risk for pulmonary embolism

  • Reduced fertility

  • Risk for heart disease?

TRAVERSE Study (Testosterone Replacement effects on Cardiovascular events and Prostate)

• ultimately, when you have large studies like this one, the potential risks of testosterone replacement therapy seem to be overblown

• whether you get placebo or testosterone, really not much difference in the risk of cardiovascular disease in these older males

Female Puberty & Menopause

Lifetime Germ Cell/Oocyte Chart in Women

• how many oocytes can be produced & how they are lost over the lifespan of a female

• oogonia divide mitotically until they have a large #

• meiosis → die off by apoptosis

  • transition from mitotic → meiotic germ cells

• 300,000 oocytes by puberty

  • as they are utilized through each menstrual cycle, they slowly decline until there’s not enough oocytes left to maintain cyclicity (the menstrual cycle)

    • happens b/w 45-50 years of age

Puberty is a Multi-Step Process

Puberty in Females

• Ages of 8-14

• Thelarche- Breast bud development

• Adrenarche (DHEAS)- initiate growth spurt, growth of axillary and pubic hair, development of libido

  • adrenarche is a hormone from adrenal glands, sulfated version

• Increased GnRH → increased LH, FSH → ovarian steroids

  • Estrogen promotes fat deposition to lead to female phenotype (breast enlargement, buttocks, thighs)

  • Estrogen closes epiphyseal plate to halt long bone growth

    • stop growing taller

    • early on, androgens accelerate that

Puberty in Females Occurs in Specific Stages

Specific age at each stage varies considerably

• going to happen in a very predictable stage specific manner

Leptin & Puberty

• #1 factor for onset of puberty is genetics

• 2nd is how much of hormone leptin is coursing through your system

• fat cells can also produce estrogens

  • these hormones have a profound impact on this region of the hypothalamus that will eventually lead to production of kisspeptin & GnRH & then subsequently change secretion of gonadotrope cells in anterior pituitary & lead to puberty

Female Hypothalamus-Pituitary-Gonadal (HPG) Axis

Hypothalamus is the master reproductive control center

• Controlled release of GnRH leads to control of FSH and LH from the anterior pituitary

  • GnRH acting on gonadotrope cells

• Gonadotrope release of gonadotropins (FSH and LH) control function of gonads

  • Hormone synthesis and secretion

  • Follicle growth and oocyte production

The Menstrual Cycle

• after puberty is initiated, will start to have changes in hormones FSH, LH, hormonal changes from anterior pituitary

• also going to change the gonadal hormones

Potential Causes of Precocious Puberty are Numerous

understand there are a lot of different forms of precocious puberty & they can be caused by multiple different reasons

Age at Puberty Onset is Decreasing

• women are coming into puberty at a younger age

• still not clear why this is happening

Endocrine Disruptors (EDs) may hasten the onset of puberty

genetics is most powerful impact

Delayed Puberty Also Has Many Potential Causes

1. Constitutional delay (late bloomer) → most common, weren’t ready genetically

2. Chronic disease

3. Hypogonadotropic hypogonadism

   • pituitary gland fails to release adequate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to stimulate the gonads

     • Thyroid

     • Pituitary tumors

     • Excessive exercise

     • Malnutrition

     • Stress

     • Depression

4. Hypergonadotropic hypogonadism occurs when the gonads (testes or ovaries) fail to produce sufficient sex hormones and the brain overproduces gonadotropins (FSH) and (LH) to compensate

• Premature ovarian insufficiency

• Fragile X

• Turner syndrome

• 17 hydroxylase or aromatase deficiency

• Chemotherapy/radiation

probably just your genes more than anything

Estrogen Secretion Changes Across Lifespan of Females (dominant hormone is females, especially during menstrual cycle)

• early on, the estrogen levels that rise during menstrual cycle might be a little more erratic

  • become regular until age is ~40-45 & then things start to become irregular again

• between 45-50, those levels will drop because there’s no more oocytes to produce follicles, & follicles produce estrogen

Gonadotropin (FSH & LH) Secretion Across Lifespan in Males and Females

Hormonal changes across the menopause transition:

1. Inhibins, AMH (MIS) decrease

2. Increased FSH release

   1. decrease in estrogen

   2. estrogen is involved in negative feedback regulation of FSH secretion

3. Estrogen decreases due to lack of follicles to recruit

4. GnRH increase due to lack of negative E feedback

5. FSH and LH increase

Early menopause suggests premature ovarian failure

• why would FSH go so high when you no longer have oocytes?

  • oocytes are in follicles → follicles make estrogen → estrogen is the negative feedback mechanism that keeps FSH levels under control

  • lose estrogen → lose ability to control FSH & it goes very high until cells become unresponsive & start shutting down

• as we near the end if our reproductive lifespan, certain changes in hormones are recognizable

Estrogen Effects are Important Throughout Life

Number of Primordial Follicles and the Chromosomal Quality of Oocytes in Relation to Age

Lifetime Female Average Fertility Rates

Conclusions:

• Available contraception works

• Women/families are delaying birth of children

Menopause: The More You Know the Better Prepared

• can’t wait too long, things will start to shut down

• understand what the physiological responses are when estrogen starts to drop

• ovarian steroids go down

Aging and Women’s Sexual and Reproductive physiology

all due to depletion of oocytes

• menopause → end of reproductive lifespan

• can’t continue to have ovarian function if there’s no oocytes to drive the process

• depletion of oocytes triggers decrease in ovarian function & once the ovary stops functioning, start seeing loss of bone, loss of ovarian steroids, etc.

• ovarian steroid: primarily estrogen, will cause a lot of downstream problems

Bone Mass Across Age

Menopause Treatments

• Hormone Replacement Therapy- make sure balanced and appropriately times (don’t wait too long)

  • Vaginal estrogen

• Hot flash management:

  • Embr Wave 2 (wearable)

  • Low dose selective serotonin reuptake inhibitors (SSRIs) (Zoloft, Prozac, etc…)

  • Gabapentin (pain management)

  • Clonidine path (blood pressure)

  • Fezolinetant (Veozah)

• Osteoporosis prevention/management

  • Vit D supplements

  • Bisphosphates

    • serious risk of low bone mass

Potential Side Effects of Hormone Replacement

• Minor

  • Breast tenderness or swelling

  • Bloating and fluid retention

  • Headaches or migraines

  • Vaginal bleeding or spotting

  • Nausea or digestive issues

  • Mood swings or depression

  • Skin irritation (if using patches, gels, or sprays)

• Major

  • Blood Clots and Stroke:

    • With oral pills rather than skin patches

  • Breast Cancer:

    • With long-term use of combined estrogen and progestin

  • Endometrial Cancer:

    • If using estrogen-only therapy

  • Cardiovascular Disease:

    • Potential for increased risk of heart attacks

  • Dementia:

    • Potential in women 65 and older taking combination HRT

Summary

• Fetal endocrine environment influences the development of the hypothalamic-pituitary-gonadal (HPG) axis

• Endocrine hormones drive developmental changes in male and female reproductive systems during in utero development, childhood, and puberty

• Fetal and post-natal hormonal programming effects brain sexual differentiation and later reproductive behavior

• Puberty advances in stages and at different rates for males and females

• Metabolic control of puberty involves leptin, ghrelin, insulin, IGF-1 and other hormones and growth factors

• Obesity, endocrine disruptors, and underlying medical conditions can impact age of puberty

• Aging-related changes in reproductive physiology leads to menopause in females and andropause in males

• There are treatments and clinical considerations for menopause and andropause, including hormone replacement therapies each with potential associated risks

ICQ #1: Which hormone conversion is essential for external male genitalia development during early fetal life?

• Estradiol to testosterone

• Testosterone to dihydrotestosterone (DHT) → forms external genitalia

• Progesterone to estrogen

• Cortisol to DHEA

• Leptin to insulin

ICQ #2: Which of the following is NOT commonly considered a potential cause of delayed puberty in females?

• Constitutional delay (late bloomer)

• Excessive exercise

• Thyroid disorders

• Increased leptin levels

• Malnutrition